Stereocontrolled synthesis of (+)-methoxyphenylkainic acid and (+)-phenylkainic acid

Article abstract of DOI:10.1021/ol103131p

The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+)-phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accom

Full text of DOI:10.1021/ol103131p

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1089–1091
Stereocontrolled Synthesis of
(þ)-Methoxyphenylkainic Acid and
(þ)-Phenylkainic Acid
Takumi Higashi, Yoichiro Isobe, Hitoshi Ouchi, Hiroto Suzuki, Yuko Okazaki,
Tomohiro Asakawa, Takumi Furuta,† Toshiyuki Wakimoto,‡ and Toshiyuki Kan*
School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
kant@u-shizuoka-ken.ac.jp
Received December 24, 2010
ABSTRACT
The efficient total syntheses of (þ)-methoxyphenylkainic acid (3) and (þ)-phenylkainic acid (4) were achieved using a rhodium carbenoid-
mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the
stereochemistry at the C-4 position as a pivotal stereogenic center.
Recently, kainoids, such as compound 1 (Figure 1), have
received significant attention due to their binding affinity
for ionotropic glutamate receptors (iGluRs). iGluRs are
involved in important neurophysiological processes, such
as memory and learning.1 Although many synthetic
investigations of kainoids have been reported to date,2
efficient synthetic methods are still strongly required.
During the pioneering investigations of the potent natural
product acromeric acid A (2),3 discovered by the Shirahama
group, it was discovered that a synthetic derivative 3
possessed more potent activity than the natural compound
2.4 Inspired by this interesting structure-activity relation-
ship, we launched an investigation into the development of
efficient synthetic methods for achieving 3 and 4. Although
several synthetic investigations of 3 and 4 have been
reported,5 few investigations have elucidated the mode
by which these compounds selectively bind to iGluRs.
Detailed biological studies would be assisted by access to
an adequate supply of the compounds via an efficient
synthetic route.
† Current address: Institute for Chemical Research, Kyoto University, Uji,
Kyoto 611-0011, Japan.
‡ Current address: Graduate School of Pharmaceutical Sciences, Univer-
sity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
(1) For selected reviews on the kainoid family, see: (a) Moloney,
M. G. Nat. Prod. Rep. 2002, 19, 597–616. (b) Moloney, M. G. Nat. Prod.
Rep. 1999, 16, 485–498. (c) Moloney, M. G. Nat. Prod. Rep. 1998, 15,
205–219. (d) Parsons, A. F. Tetrahedron 1996, 52, 4149–4174.
(2) For recent examples of the enantioselective total synthesis of
kainic acid, see: (a) Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.;
Chida, N. Org. Lett. 2010, 12, 5756–5759. (b) Farwick, A.; Helmchen, G.
Org. Lett. 2010, 12, 1108–1111. (c) Tomooka, K.; Akiyama, T.; Man, P.;
Suzuki, M. Tetrahedron Lett. 2008, 49, 6327–6329. (d) Sakaguchi, H.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711–1714. (e) Jung,
Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem.
2007, 72, 10114–10122. (f) Chalker, J. M.; Yang, A.; Deng, K.; Cohen, T.
Org. Lett. 2007, 9, 3825–3828. (g) Sakaguchi, H.; Tokuyama, H.;
Fukuyama, T. Org. Lett. 2007, 9, 1635–1638. (h) Pandey, S. K.;
Orellana, A.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665–
5668. (i) Poisson, J.-F.; Orellana, A.; Greene, A. E. J. Org. Chem. 2005,
70, 10860–10863. (j) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2005, 7, 4337–4340.
The heart of our synthetic plan is illustrated in Scheme 1.
We envisioned that two carboxylic acid moieties could be
(3) (a) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron Lett. 1998, 39, 707–710. (b)
Horikawa, M.; Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1993,
34, 331–334. (c) Barco, A.; Benetti, S.; Pollini, G. P.; Spalluto, G.;
Zanirato, V. Gazz. Chim. Ital. 1993, 123, 185–188. (d) Konno, K.;
Hashimoto, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T. J. Am.
Chem. Soc. 1988, 110, 4807–4815. (e) Baldwin, J. E.; Li, C. S. J. Chem.
Soc., Chem. Commun. 1988, 4, 261–263. (f) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. J. Am. Chem. Soc. 1987, 109, 5523–5524. (g) Konno, K.;
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r
10.1021/ol103131p
2011 American Chemical Society
Published on Web 02/10/2011

Scheme 2. Synthesis of (þ)-Phenylkainic Acid (4)
Figure 1. Structures of kainoids 1, 2, 3, and 4.
Scheme 1. Retrosynthetic Analysis of 3 and 4
readily elaborated from cyano groups with retention of the
oxidation state. The upper and lower nitriles would be
incorporated by an SN2 reaction and the Strecker-type
reaction of 5, respectively. After incorporation of the
amine group in 6 by our Ns-amide 7,6 ring closure by
reaction of the nitrogen atom with the aldehyde would give
5 with the desired stereochemistry. Switching the stereo-
chemistry of the side chain at the C-3 position of 5 by a
ring-opening reaction of 6 followed by recyclization would
bea crucialstep. Because thestepwiseoxidative cleavageof
8 would provide a stable trans-substituted aldehyde 6, a
stereocontrolled synthesis of 8 would be required. Re-
cently, we developed an efficient rhodium carbenoid-
mediated intramolecular C-H insertion7 of aryldiazoace-
tate, which possessed a chiral auxiliary.8,9 We envisioned
that applying this strategy to the intermolecularreaction of
9 and cyclohexadiene 10 would enable construction of 8
with the correct stereochemistry.10 Although similar C-H
insertion reactions of the methyl ester derivatives 9 and 10
have been reported, the enantiomeric excess has not been
satisfactory.9 Thus, our strategy for the synthesis of phe-
nylkainic acid commenced with the incorporation of a
chiral auxiliary into the phenylacetic acid.
Preparation of the diazoester 9a was performed by
condensation of phenylacetic acid 12 with the chiral
auxiliary 118 and the subsequent diazo transfer reaction
(Scheme 2). Upon treatment of 9a and 10 with 0.2 mol %
of the Davies catalyst,11 the C-H insertion reaction
proceeded smoothly to afford, exclusively, a diene 13 in
82% yield. Next, monoselective oxidative cleavage of the
diene 13 was accomplished by treatment with ozonolysis
at -78 °C. After checking for the disappearance of the
starting material by TLC, subsequent addition of NaBH4
gave the corresponding primary alcohol. Without purifi-
cation, subjection to acidic cyclization provided a lactone
(5) (a) Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036–4037. (b) Itadani, S.;
Takai, S.; Tanigawa, C.; Hashimoto, K.; Shirahama, H. Tetrahedron
Lett. 2002, 43, 7777–7780. (c) Baldwin, J. E.; Bamford, S. J.; Fryer,
A. M.; Rudolph, M.; Wood, M. E. Tetrahedron 1997, 53, 5255–5272. (d)
Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314–2315. (e)
Horikawa, M.; Shirahama, H. Synlett 1996, 95–96. (f) Hashimoto, K.;
Shirahama, H. Tetrahedron Lett. 1991, 32, 2625–2628.
(6) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301–1304.
(7) For a recent review of Davies’s C-H functionalization, see:
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424.
(8) (a) Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.;
Fukuyama, T.; Kan, T. J. Am. Chem. Soc. 2008, 130, 16854–16855.
(b) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
8112–8113. (c) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003,
1028–1030.
€
(10) (a) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725–1731. (b)
Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1,
233–236.
(11) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075–
(9) For a similar chiral auxiliary approach, see: Davies, H. M. L.;
Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L. J. Am. Chem. Soc. 1993,
115, 9468–9479.
9076.
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Org. Lett., Vol. 13, No. 5, 2011

14 as a 1:1 mixture of the diastereoisomers. Next, oxidative
cleavage of the olefin 14 proceeded with the concomitant
epimerization at the R-position of the aldehyde to give,
predominantly, the trans lactone 15. In this reaction, the
absence of triethylamine base resulted in a 1:1 mixture of
the cis and trans lactones. After protection of the aldehyde
with ethyleneglycol, DIBAL reduction of the lactone and
conversion of the lactol to the acetate gave 16. Upon
Scheme 3. Synthesis of (þ)-MFPA (3)
treatment of 16 with Ns-NH2 and BF3 OEt2 at room
3
temperature, an oxonium cation-mediated amination re-
action proceeded smoothly to afford 17 in 85% yield.
Selective reduction of the aminal of 17 was performed
by treatment with DIBAL to give the desired primary
alcohol 18 without loss of the acetal moiety. Treatment
of 18 under acidic conditions, alcoholysis of the acetal,
and subsequent cyclization with the Ns-amide pro-
ceeded smoothly to provide the aminal 19. Upon treat-
ment of 19 with BF3 OEt2 and TMSCN, nucleophilic
3
alkylation of cyanide to the nitrobenzensulfonylimi-
nium ion intermediate occurred from the less hindered
β-face of the pyrrolidine ring to provide the desired
aminonitrile as a single diastereomer. Upon treatment
of 20 with acetone cyanohydrine12 and DMEDA,13 the
desired Mitsunobu reaction proceeded smoothly to
afford 21, which possessed the desired stereochemistry
for 4. After deprotection of the Ns group by treatment
with PhSH and base,14,15 acidic hydrolysis of the cyano
groups was carried out in a sealed tube to give the
desired phenylkainic acid 4, the spectral data of which
(1H NMR, 13C NMR, IR, and HRMS) were in full
agreement with those reported to date.5e
Next, we turned our attention to the synthesis of (þ)-
methoxyphenylkainic acid (MFPA, 3). As shown in
Scheme 3, we employed a similar procedure that was
employed for the synthesis of 4. Starting from methox-
yphenylacetic acid (22), using an intermolecular C-H
insertion, between 9b and 10, a stepwise oxidative
cleavage of diene 23 and Strecker-type reaction of the
Ns-iminium salt derived from 26 as key steps provided 3
in a similar selectivity and yield.16 Investigations of the
biochemistry and biological properties of 3 and 4 are
ongoing in our laboratory, and the results will be
reported in detail soon.
In conclusion, a stereoselective total synthesis of 3 and 4
was accomplished by an intermolecular Rh-catalyzed
C-H insertion between 10 and phenylacetic acid deriva-
tives 9b and 9a. The asymmetric center at the benzylic
position permitted efficient incorporation of the three
sequential stereochemistries on the pyrrolidine ring.
Acknowledgment. This work was financially supported
by the Takeda Science Foundation, the Naito Foundation,
the Nagase Science and Technology Foundation, and a
Grant-in-Aid for Scientific Research on Priority Areas
12045232 from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
(12) Wilk, B. K. Synth. Commun. 1993, 23, 2481–2483.
(13) For a DMEDA mediated Mitsunobu reactions, see: Sugimura,
T.; Hagiya, K. Chem. Lett. 2007, 36, 566–567.
(14) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. Organic Synthesis,
Vol. X; Wiley: New York, 2002; pp 482-487. (b) Fukuyama, T.; Jow
C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–6277.
(15) For reviews of Ns-strategy, see: (a) Kan, T.; Fukuyama, T. Yuki
Gosei Kagaku Kyokaishi 2001, 59, 779–789. (b) Kan, T.; Fukuyama, T.
Chem. Commun. 2004, 353–360.
Supporting Information Available. Experimental de-
tails and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) For detailed experimental conditions and spectral data, see
Supporting Information.
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